|Year : 2010 | Volume
| Issue : 3 | Page : 465-469
|Peritumoral lymphatic vessel density as a prognostic parameter in endometrial carcinoma: An immunohistochemical study
Hala K Maghraby1, Ashgan I Elsarha1, Reda S Saad2
1 Department of Pathology, MRI Alex University, Toronto, ON,Canada
2 Sunnybrook Health Science Centre, University of Toronto, Toronto, ON, Canada
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|Date of Web Publication||22-Oct-2010|
| Abstract|| |
Context: Lymphatic invasion and nodal metastasis play a major role in the spread and prognosis of endometrial adenocarcinoma (EC). Aims: In this study, we investigate tumor lymph-angiogenesis, detected by D2-40, as a predictive marker for the risk of lymph node (LN) metastasis and its relation to other prognostic parameters in EC. Materials and Methods: Fifty-five cases of EC treated with total hysterectomy and pelvic LN dissection were reviewed. All cases were immunostained for D2-40. Positively stained microvessels (MV) were counted in densely lymphovascular foci (hotspots) at X 400 field (0.17 mm2). Statistical Analysis: Statistical analysis was performing using Chi square "X 2" test. Results: Lymphovascular invasion was detected in 20 / 55 patients by D2-40 and 14 / 55 by routine hematoxylin and eosin (H and E). Peritumoral lymphatic vessel (LV) count was significantly higher than intratumoral LV count (17 + 7 versus 5 + 4 / 0.17 mm 2 , P < 0.01). Peritumoral D2-40 lymphovascular counts correlated significantly with FIGO grade (P < 0.001), lymphovascular invasion (P = 0.001) and LN metastases (P = 0.005). However, it showed non-significant correlation with peritoneal wash positivity (P = 0.830) and stage of the disease (P = 0.341). Intratumoral lymphovascular invasion detected by D2-40 showed significant correlation with LN metastases (P < 0.01). Conclusions: Our study shows that assessing LVD with D2-40 in the endometrial carcinoma might be a valuable parameter for predicting patients having an increased risk of developing of metastatic disease. In addition, D2-40 increases the frequency of detection of lymphatic invasion relative to routine H and E stain.
Keywords: D2-40 immunostaining, endometrial carcinoma, lymphatic vessel density
|How to cite this article:|
Maghraby HK, Elsarha AI, Saad RS. Peritumoral lymphatic vessel density as a prognostic parameter in endometrial carcinoma: An immunohistochemical study. Indian J Pathol Microbiol 2010;53:465-9
|How to cite this URL:|
Maghraby HK, Elsarha AI, Saad RS. Peritumoral lymphatic vessel density as a prognostic parameter in endometrial carcinoma: An immunohistochemical study. Indian J Pathol Microbiol [serial online] 2010 [cited 2021 Jul 24];53:465-9. Available from: https://www.ijpmonline.org/text.asp?2010/53/3/465/68278
| Introduction|| |
Tumor angiogenesis, i.e. formation of new blood vessels associated with a neoplasm, is essential for tumor growth and metastases and is regarded as one of the most important events occurring in the neoplastic process. ,,, Tumor-associated vessels are structurally and functionally abnormal, with increased permeability, delayed maturation and potential for rapid proliferation. , These vascular defects facilitate the lympho-hematogenous spread of tumor cells. 
Lymph node metastasis is the first step in the spread of the disease, represents a major criterion for evaluating the prognosis and the need for additional adjuvant therapy. , Little is known regarding lymph-angiogenesis and the mechanisms through which tumor cells gain entry into the lymphatic system.  Lymphatic spread of the disease is assumed to occur through cancer cell permeation of tumor lymphatics, thus reaching the regional lymph nodes. , However, it is unclear whether lymphatic dissemination occurs as a result of cancer cell infiltration of pre-existing lymphatic vessels or newly formed ones, originating from those of the normal surrounding tissues. ,
Lymph-angiogenesis has been difficult to investigate because there was a lack of specific antibodies recognizing the lymphatic endothelium.  Most available endothelial markers used to assess intratumoral micro vessel density, a reflection of tumor angiogenesis, stained both lymphatic and vascular vessels without discrimination.  Recently, lymphatic endothelial specific markers have become available, which facilitate analysis of lymph-angiogenesis in cancer. , D2-40, an IgG2a monoclonal antibody, was generated against an oncofetal membrane antigen M2A and identified in ovarian carcinoma cell lines and germ cell neoplasia.  D2-40 was reported to be a specific marker for lymphatic endothelium in normal and neoplastic tissue.  D2-40 has shown to stain endothelium of lymphatic vessels and lymphangiomas but negative in hemangiomas. 
This study aims to investigate lymphatic vessel density (LVD) and lymphovascular invasion, using monoclonal antibody D2-40, as predictive marker for the risk of lymph node metastases in endometrial cancer patients.
| Materials and Methods|| |
Formalin-fixed, paraffin-embedded specimens from 55 patients with endometrial carcinoma were retrieved from the files of the department of pathology of a medical research institute in the period from January 1999 to December 2004. All patients underwent total hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymph node dissection.
All cases were reviewed to confirm the diagnosis and evaluated for histologic Federation of International Gynecological Oncologists (FIGO) grade, depth of myometrial invasion, presence of lymphovascular invasion, lymph node metastasis and stage of the disease. Lymphovascular invasion was considered evident if at least one tumor cell cluster was clearly visible inside the vascular space. The stage was determined using American Joint Committee on Cancer (AJCC) staging system.  The carcinomas were classified using a three grade system (FIGO grade): Grade 1 carcinomas showed glandular formation in more than 95% of the tumor, Grade 2 carcinomas showed a solid growth pattern in 5-50% and Grade 3 carcinomas showed a solid pattern in more than 50%. One paraffin block with the maximum bulk of tumor and maximum depth of invasion was chosen from each case for immunohistochemical studies.
Two m m-thick sections from the paraffin-embedded tissue blocks were deparaffinized in xylene and rehydrated in a descending ethanol series. Sections were incubated for five minutes in 3% hydrogen peroxide to quench endogenous tissue peroxidase. The sections were immunostained for D2-40 monoclonal antibody (clone D2-40, signet laboratories, Dedham, MA, USA) at a 1:50 dilution. Heat-induced epitope retrieval techniques were used for antigen retrieval as follows: citrate buffer (pH 6.0) and a steamer at 120 o C for five minutes. The Ventana immunostainer and iView DAB detection kit (Ventana medical systems, Tucson, AZ) were used. Slides were counterstained with hematoxylin, cleared in alcohol and xylene and mounted. Lymphatic vessels in the deeper part of the myometrium were used as positive internal controls. Appropriate negative control was run for each batch of slides.
Counting of Lymphatic Vessel and Scoring of Microvessel Densities
Sections were first examined at low magnification (Χ100) to identify areas with most intense staining and apparent highest density of MV (hotspot).  Three areas of hotspots were selected by three pathologists and then independently evaluated the slides for MV counting using 400Χ magnification (0.17 mm 2 field) without the knowledge of patient status. In the absence of apparent hotspots, three or more randomly selected areas were counted. For lymphatic vessel density (LVD), intratumoral and peritumoral lymphatic MV densities were counted separately. Intratumoral lymphatic vessels were defined as vessels within the main tumor mass, surrounded by tumor cells, without muscle layer or red blood cells (RBCs) in their lumen. Vessels more than one high power field (Χ250) away from the invasive tumor front were considered peritumoral lymphatic vessels. Single immunoreactive endothelial cells, or endothelial cell clusters separate from other MVs, were counted as a vessel.  The highest number of vessels counted was recorded and used in the statistical analysis. Discordant cases were recounted and consensus resolved any discrepancy of more than 10% of the MV count. LVD was classified into low (<10 vessels / high-power fields), moderate (10-15 vessels / HPF) and high (>15 vessels / HPF).
Statistical analysis was performing using Chi square "c2" test; tumor grade, lymphovascular invasion, lymph node metastases, peritoneal wash status and stage of the disease were compared with lymphovascular count. A P value equal to or less than 0.005 was considered significant.
| Results|| |
The mean patient age was 61.2 ± 10.6 years with an age range of 40 to 88 years. All our cases were endometrioid type of endometrial adenocarcinoma, classified according to FIGO grade as follows: 11 cases FIGO Grade 1; 28 cases FIGO Grade 2 and 16 cases FIGO Grade 3. Fourteen cases had positive lymphovascular invasion and nine cases had positive regional lymph node metastases. Pelvic washing was positive in 11 cases. Pathologic staging was as follows: 20 cases Stage I b; 10 cases stage I c; seven cases Stage II; nine cases Stage IIIa; and nine cases Stage IIIc. Peritumoral and intratumoral vascular densities (either lymphatics or blood vessels) were carefully studied in H and E sections from all cases and it was found that peritumoral vascular density was more prominent than intratumoral vessel density. However, differentiation between lymphatics and small capillaries was almost difficult.
D2-40 immunostained similar tissue sections showed that D2-40 positive lymphatic vessels were seen within areas of hyperplastic endometrium adjacent to endometrial adenocarcinoma and in the stromal of endometrial polyps (three cases) [Figure 1]. However, the number of lymphatic vessels in the hyperplastic endometrium (6 ± 4 "range 2-9") is significantly lower than those identified in endometrial adenocarcinoma (15 ± 7 / 0.17 mm 2 "range 8-23"); P < 0.05.
|Figure 1 :D2-40 stains lymphati c vessels in hyperplasmati c endometrium (a) and in endometrial polyp. Negati ve staining in thickened blood vessels (b) (immunohistochemistry, ×400)|
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D2-40 stained peritumoral lymphatic vessels in all our cases (100%), [Figure 2]a and b. It stained only lymphatic endothelial cells and was negative in blood vessels [Figure 1]a and b. The mean numbers of LV identified by D2-40 were 15 ± 7/0.17 mm 2 (range, 8-23). However, intratumoral lymphatics were identified in only 16/55 (29%) of our cases. There was a significant correlation between peritumoral and intratumoral lymphatic densities (15 ± 7 versus 5 ± 3, P < 0.05). Intratumoral lymphatics were small and flattened, in contrast, peritumoral ones were enlarged and dilated.
There was significant correlation of peritumoral D2-40 LVD with FIGO grade (P < 0.001), lympho-vascular invasion (P = 0.001) and lymph node metastases (P = 0.005) [Table 1]. However, it was not-significantly correlated with peritoneal wash status (P = 0.830) and stage of the disease (P = 0.341) [Table 1].
|Figure 2 :D2-40 expression in endometrial adenocarcinoma. Strong staining of D2-40 in peritumoral (a) and in intratumoral lymphati cs (b) (Immunohistochemistry, ×400)|
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|Table 1 :Correlati on between peritumoral microvascular density "stained by D2-40" and prognosti c pathologic parameters|
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Lymphovascular invasion was detected in 20 / 55 (36%) patients by D2-40 [Figure 2]a and 14/55 (25%) by routine hematoxylin and eosin stain. Lymphovascular invasion detected by D2-40 was significantly correlated with LVD (P < 0.05) and lymph node status (P < 0.01)
| Discussion|| |
The lymphatic system is the primary pathway of metastasis for most human cancers and the extent of lymph node involvement is a crucial prognostic factor for the patient outcome. There have been few studies investigating the significance of lymph-angiogenesis as an indicator for lymph node metastases, due to lack of specific lymphatic markers.  Recently, D2-40 has been demonstrated to recognize tumor-associated lymphatic vessels in many tumors. , In this study, we investigated the D2-40 LVD as a potential prognostic indicator in a series of endometrial cancer patients.
In contrast to the process of angiogenesis, less information is available in regards to lymph-angiogenesis. , Lymph-angiogenesis within tumors is believed to facilitate tumor growth by draining waste products of metabolism and promoting lymphatic metastases.  However, the presence of intratumoral lymph-angiogenesis is a subject of controversy. Some studies reported that solid tumors do not have lymphatic vessels, due to the increased interstitial pressure created by the proliferating cancer cells, whereas lymphatics at the tumor margin facilitate spread of tumor cells. , In contrast, intratumoral lymphatics were identified in solid tumors such as colorectal carcinoma, , melanoma,  pancreatic adenocarcinoma,  and head and neck squamous cell carcinoma. , Intratumoral lymphatics were also found to be correlated with locoregional recurrence and lymph node metastases. ,
In our study, the presence of intratumoral lymphatic vessels was identified in 29% of cases and showed a significant correlation with FIGO grade and lymph node metastases. Similar to previous studies, we found that most of intratumoral lymphatics are small and flattened. , In contrast, peritumoral lymphatic vessels are enlarged and dilated. ,
Other investigators have proposed peritumoral lymphatic vessel density as a prognostic factor in gynecologic tumors.  In breast cancer, there is a significant correlation between LVD / lymphovascular invasion and axillary lymph node metastasis with poor prognosis. ,, Similarly, VEGF-D emerged as strong predictors for poorer survival and correlated with lymph node metastasis and peritoneal spread in ovarian carcinoma.  In contrast, using podoplanin as a lymphatic marker, LVD failed to show influence on the progression of epithelial ovarian cancer. , However, in endometrial cancer, LVD using VEGF-3 or VEGF-C- correlates with lymph node metastases and poor disease-free five-year survival. , Our results demonstrate that using D2-40, LV counts in endometrial carcinoma correlated significantly with FIGO grade, presence of lymphovascular invasion and lymph nodes metastases, but is not significantly correlated with peritoneal wash and stage of the disease. Using multivariate analysis, D2-40 LVD correlated significantly with lymphovascular invasion, lymph node metastases, and independent of tumor stage. These results are in accordance with angiogenesis and lymph-angiogenesis being crucial factors in the metastatic process and thus for the progression of a malignant disease.
The contradicting results about the role of lymph-angiogenesis in tumor progression may be due to differences in patient selection, methodology and/or the types of tumors included in the analyses. However, the main reason for the controversial results may be the previous lack of lymphatic vessel markers. Some investigators have used various lymphatic markers for their studies, such as LYVE-1 and VEGFR-C. LYVE-1 which are believed to be a specific marker for lymphatic vessels; however, its sensitivity and specificity for lymphatic vessels has been questioned.  Vleugel et al.  and Williams et al.  Failed to detect lymph-angiogenesis in breast cancer using LYVE-1 as a marker for lymphatic vessels. A recent study also failed to detect lymphatics within non-small cell lung carcinoma using LYVE-1, while they were identified using podoplanin.  Both LYVE-1 and VEGFR-3 are not completely specific for lymphatic endothelium in the tumor because they also stain endothelial blood vessels. , Tumor lymph-angiogenesis and lymphatic metastasis are complex mechanisms which can differ significantly in tumors of different types or anatomic locations.  Intratumoral lymphatics are restricted only to certain cancer types and they may have prognostic significance. In our study, we detected intratumoral lymphatic vessels in 29% of our cases, which is less than what was previously reported in colorectal adenocarcinoma. 
Lymphovascular invasion has long been considered an important prognostic indicator of cancer. Our results showed that D2-40 immunostaining is a useful immunohistochemical marker for identifying the presence of lymphatic invasion. Regarding the comparison of the results of H and E staining and CD2-40 immunohistochemical staining, it was found that lymphovascular invasion was detected in 20 cases (36%) by using CD2-40 immunostaining in contrast to only 14 H and E stained cases (25%). This means that it is difficult to detect lymphovascular invasion by H and E stains; and, D2-40 can strongly label lymphatic endothelial cells, highlighting the presence of lymphatic invasion in the tumors, leading to increase the detection rate of lymphovascular invasion. D2-40 was reported to be a useful marker for the identification of tumor emboli in lymph vessels of many primary tumors. , These results were in accordance with a recent Mannelqvist et al. study,  which found that 31% of their cases showed lymphatic invasion by using CD2-40 immunostain. They also reported that immunohistochemical markers of blood and lymphatics increase the sensitivity and specificity of what should be considered as a real vascular space. Similar to our results, several studies have reported a strong correlation between lymphatic vessel invasion and lymph node involvement in gynecological cancers. ,, D2-40 highlights lymphatics and outlines the tumor emboli otherwise indiscernible by hematoxylin and eosin stain and increases the detection rate of lymphatic invasion by 16% in melanoma patients.  In a series of 374 breast cancer specimens, lymphovascular invasion, using podoplanin as marker, correlated significantly with lymph node metastasis and appeared to be an independent prognostic parameter for disease-free and overall survival.  In our study, D2-40 showed good detective results for lymphovascular invasion and was significantly correlated with lymph node metastases.
Although pre-existing peritumoral lymphatics can provide a sufficient route for tumor spread, recruitment of lymphatic vessels into the close proximity of a tumor may increase the propensity of the tumor to metastasize.  Therefore, increased lymphatic vessel density as well as the presence of intratumoral lymphatics should be regarded as an additional pathway for metastases.  In our study, we demonstrate that endometrial cancers with high peritumoral and intratumoral lymph-angiogenesis are significantly more associated with lymphovascular invasion and lymph node metastases, since these factors provide the tumor cells with more opportunities to enter into lymphatic vessels with more metastases.
In contrast to a previous study,  we identified D2-40 positive lymphatic vessels in the benign proliferative endometrium and endometrial hyperplasia. However, the number of lymphatics in these benign conditions was significantly lower than in endometrial adenocarcinomas. In addition, we identified D2-40 stained lymphatics in endometrial polyps. This supports the potential metastatic capability of carcinoma arising in endometrial polyp. Similar to the same study, D2-40 positive lymphatics were identified within the normal myometrium.
In conclusion, we observe that peritumoral lymph-angiogenesis occurs in the endometrial carcinoma and correlates with high grade, lymphovascular invasion and lymph node metastases. Therefore, assessing LVD with D2-40 in the endometrial carcinoma might be a valuable parameter for predicting patients having an increased risk of developing of metastatic disease. In addition, D2-40 increases the frequency of detection of lymphatic invasion relative to routine hematoxylin and eosin stain.
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Ashgan I Elsarha
47, st.314 from Mostafa Kamel, Smouha, Alex, Egypt
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
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